NM_017763.5:c.1148T>C (p.Met383Thr) is a missense variant in RNF43, a gene in which primarily truncating variants cause serrated polyposis syndrome through loss of function.1 This variant is extremely rare in population databases, with an allele frequency of 0.00121% in gnomAD v2.1 (2/165,256 alleles) and 0.00065% in gnomAD v4.1 (10/1,546,206 alleles), with no homozygotes observed.2 Multiple lines of computational evidence predict a benign effect: REVEL score 0.029 (benign-leaning), BayesDel score -0.829 (negative), and SpliceAI predicts no splice alteration (max delta 0.01).3 This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (ClinVar Variation ID: 1938526).4 No variant-specific functional studies, segregation data, de novo observations, or case-control data are available for this variant. The variant does not localize to a statistically significant mutational hotspot or well-characterized functional domain; residue 383 lies outside the RNF43 RING finger domain (residues ~270-313).
RNF43
Final classification
Likely Benign
RNF43 c.1148T>C · p.Met383Thr
RNF43
NM_017763.5:c.1148T>C (p.Met383Thr) is a missense variant in RNF43, a gene in which primarily truncating variants cause serrated polyposis syndrome through loss of function.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP1BP4
Likely Benign
RNF43 c.1148T>C
PM2 + BP1 + BP4
→
Likely Benign
Gene diagram
· NM_017763.5 · variants mapped to exon structure
RNF43
NM_017763.5
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_017763.5:c.1148T>C is extremely rare in population databases. In gnomAD v2.1 exomes, the allele frequency is 0.00121% (2/165,256 alleles, 0 homozygotes). In gnomAD v4.1, the allele frequency is 0.00065% (10/1,546,206 alleles). Absent from gnomAD-Canada. This is well below the 0.1% PM2 threshold for a rare variant absent from population controls.
gnomAD v2.1: AF = 1.21e-05 (0.00121%)2/165256 alleles
✓
BP1
supporting
Benign
NM_017763.5:c.1148T>C is a missense variant in RNF43, a gene for which primarily truncating variants (frameshift, nonsense) are known to cause disease. RNF43 loss-of-function via truncating mutations is the established mechanism for serrated polyposis syndrome. BP1 applies to missense variants in genes where the primary disease mechanism is truncating/LoF.
RNF43 disease mechanism is primarily loss-of-function via truncating variantsgermline LoF is the established mechanism for serrated polyposis syndrome.
✓
BP4
supporting
Benign
Multiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.029 (strongly benign-leaning), BayesDel score is -0.829 (negative/benign), and SpliceAI predicts no splicing impact (max delta = 0.01). All three independent in silico predictors are concordant for a benign effect.
REVEL: 0.029 (benign-leaningwell below 0.5 threshold).BayesDel: -0.829 (negative
Assessed · not applied
Pathogenic
PS1
No alternate nucleotide change at c.1148 resulting in the same p.Met383Thr amino acid substitution has been identified as a previously established pathogenic variant.
PS2
No de novo observation has been reported for NM_017763.5:c.1148T>C.
PS3
No variant-specific functional data exists for NM_017763.5:c.1148T>C (p.Met383Thr).
PS4
No case-control prevalence data comparing affected versus unaffected individuals is available for NM_017763.5:c.1148T>C.
PM1
Residue 383 is not a statistically significant mutational hotspot per cancerhotspots.org, and position 383 lies outside characterized functional domains of RNF43.
PM5
No comparator missense variants at amino acid residue 383 have been identified.
PM6
No de novo report exists for NM_017763.5:c.1148T>C.
PP1
No cosegregation data is available for NM_017763.5:c.1148T>C.
PP2
RNF43 is a tumor suppressor gene where truncating and loss-of-function variants are the primary disease mechanism for serrated polyposis syndrome.
PP3
Multiple lines of in silico computational evidence predict a benign effect.
PP4
No patient phenotype or clinical data is available for this case.
PP5
No reputable source has reported NM_017763.5:c.1148T>C as pathogenic.
Benign
BA1
The allele frequency of NM_017763.5:c.1148T>C is 0.00121% in gnomAD v2.1, far below the 1% BA1 threshold for a common benign polymorphism.
BS1
The allele frequency of NM_017763.5:c.1148T>C is 0.00121% in gnomAD v2.1, well below the 0.3% BS1 threshold.
BS2
No observation of NM_017763.5:c.1148T>C in a healthy adult individual without disease has been reported.
BS3
No well-established functional studies demonstrate that NM_017763.5:c.1148T>C has no deleterious effect.
BS4
No segregation data is available for affected family members.
BP2
No data regarding observation in trans with a pathogenic variant is available.
BP5
No alternative molecular basis for disease has been identified in a case harboring NM_017763.5:c.1148T>C.
BP6
No reputable source reports NM_017763.5:c.1148T>C as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.46744e-06; MAF= 0.00065%, 10/1546206 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 8.55746e-05; MAF= 0.00856%, 7/81800 alleles, homozygotes = 0); grpmax FAF= 3.948e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.21024e-05; MAF= 0.00121%, 2/165256 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 7.06314e-05; MAF= 0.00706%, 1/14158 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00065%
· 10 / 1,546,206
0 hom · FAF 0.0039%
0 hom · FAF 0.0039%
South Asian 7 / 81,800 |
0.0086% |
East Asian 2 / 43,070 |
0.0046% |
European (non-Finnish) 1 / 1,144,326 |
8.7e-05% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 2 / 165,256
0 hom
0 hom
East Asian 1 / 14,158 |
0.0071% |
South Asian 1 / 19,766 |
0.0051% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1938526)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.029. BayesDel score = -0.828496.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RNF43, a ubiquitin ligase, is mutated in various cancers including gastrointestinal and gynecological cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links